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14 new CRUK Oxford Centre Development Fund Awardees

The CRUK Oxford Centre are pleased to announce the 14 projects that have been selected to receive pump-priming funds. This unique scheme aims to support collaborative projects in cancer research which are a key area of activity for the Centre.

Please see a summary of the awardees and their projects below.

Tom Agnew, Sir William Dunn School of Pathology

ARH3 as a potential new biomarker in breast, ovarian and pancreatic and prostate cancer

To protect the genome from damage, organisms have evolved a cellular defence mechanism termed the DNA damage response. Exploiting DDR pathways to specifically target and kill cancer cells has become an attractive therapeutic avenue of cancer research. This is exemplified by the synthetic lethal interaction between PARP inhibition and BRCA1 or BRCA2-deficient tumours. PARP inhibitor drug resistance is a major issue for treating these cancers. This project will investigate the ARH3 enzyme as a target of reversing this resistance.

 

Elizabeth Mann et al., The Kennedy Institute of Rheumatology, NDORMS

Ex vivo phenotyping of Th17 cells from colorectal cancer patients

Although the immune system is critical in protecting against cancer development, inflammation can worsen disease. Impairing Th17 cells, a subset of CD4+ T cells, reduces tumour burden in mouse models of colorectal cancer (CRC) indicating that Th17 signalling may have novel biomarker and/or therapeutic utility. This project will investigate if Th17 cells are different in number and phenotype in clinically-relevant subclasses of CRC tumours – thus making them potential biomarkers

 

Kourosh Honarmand Ebrahimi & James McCullagh, Department of Chemistry, Chemistry Research Laboratory

Metabolomics investigation of an emerging immunometabolic pathway linking viral infection and inflammation to cancer

The activity of the antiviral enzyme radical S-adenosylmethionine (SAM) containing domain 2 (RSAD2) (also known as viperin) plays a key immunometabolic role in supporting immune function to fight a wide range of viruses. In tumour microenvironment, this activity could support tumorigenesis and tumour development via different mechanisms. In this project, the team will use a variety of analytical methods, including metabolomics and 13C tracer studies, to investigate how the immunometabolic function of RSAD2 supports cancer cell proliferation.

 

Linna Zhou, The Ludwig Institute & Department of Chemistry

Engineered gastrointestinal tissues to investigate the influence of enteric neurons in cancer progression

It has been increasingly recognised that the interactions between neurons and cancer cells, and neurons and immune cells, are important in cancer initiation, progression and metastasis. This project will use an engineering approach to generate 3D GI tissues with naturalistic cellular architecture to recapitulate the interactions of enteric neurons, immune cells and epithelial cells during cancer development. This is to assess how cancer cells migrate along neurons and how neuro-immune interactions shape the tumour microenvironment to facilitate the growth and migration of cancer cells.

 

Mariolina Salio & Graham Collins, Human Immunology Unit & Department of Haematology, Oxford University Hospitals

Immune microenvironment signatures predictive of response in patients with classical Hodgkin Lymphoma treated with checkpoint inhibitors

A major goal in the treatment of classical Hodgkin Lymphoma (cHL) is to reduce the burden of chemotherapy and radiotherapy with its associated short- and long-term toxicities, whilst maintaining high rates of cure. PD1/PD-L1 inhibitors are associated with high response rates. In solid tumours, the mechanism of action of PD1/PD-L1 inhibitors is believed to be mediated by enhanced activation of tumour specific CD8+ T cells. In cHL few CD8+ T cells are present in the tumour microenvironment, so the mechanism of action of PD1 inhibitors in this disease is still unclear. This project will investigate changes in the tumour microenvironment in biopsy material from patients with cHL treated with PD1/PD-L1 inhibitors, to identify signatures which might correlate with the therapeutic effect of these drugs.

 

Karthik Ramasamy & Ross Sadler, Department of Haematology, Oxford University Hospitals & Nuffield Department of Medicine

Post translational modification of free light chains as a biomarker for progression from monoclonal gammopathy of undetermined significance to myeloma

A pilot study to characterise post translational modifications of serum free light chains in both patients with MGUS and myeloma. A full summary of this project can be found here.

 

Monica Olcina et al., MRC Oxford Institute for Radiation Oncology, Department of Oncology

C5aR1 as a biomarker in ovarian cancer – Towards the development of radioligands for imaging and therapy of C5aR1 expressing tumours 

This project will assess C5aR1 as a biomarker to support the development of radioligands for molecular imaging and therapy of C5aR1 expressing tumours. Emerging evidence indicates that C5aR1 signalling stimulates ovarian cancer growth through regulation of oncogenic PI3K/AKT signalling. This project is investigating C5aR1 expression in a range of human ovarian cancer and healthy tissues and will also establish C5aR1 overexpression and knockdown cell lines to be used as tools in the development of radioligands (synthesised by collaborators). In the future, these radioligands will be preclinically tested for selective targeting and visualisation of C5aR1-expressing tumours – with ultimate testing in future clinical trials.

 

Ricardo Fernandes, Nuffield Department of Medicine

Development of a new approach to target FLT3 signalling in AML

This project will develop protein molecules to reduce signalling by the FLT3 receptor in myeloid cells. Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, and approximately a third of patients with AML present a heterogeneous group of activating FLT3 gene mutations. Enhanced FLT3 activity contributes to abnormal proliferation and differentiation of myeloid cells. Despite representing an attractive therapeutic target, small molecule inhibitors of FLT3 have achieved mixed results in clinical trials, partly driven by the diversity of FLT3 gene mutations and escape variants. This project will investigate a new approach for suppressing receptor signalling.

 

Simon Carr & Wojciech Barczak, Department of Oncology

Tumour specific neo-antigens derived from the non-coding genome

Cancers use a diverse array of mechanisms to evade the immune system such as down-regulating immune checkpoint pathways, and the development of therapeutic antibodies targeting immune checkpoints (such as anti-PD1 and CTLA4) represents one of the most important breakthroughs in cancer therapy. This project will look at the contribution of the non-coding genome to the tumour antigen landscape. It will use a novel method to manipulate the antigen landscape on tumour cells, by blocking PRMT5 activity, which we have shown to be important in regulating the expression of a proportion of the non-coding genome.

 

Andrew Blackford, Department of Oncology

Characterising short linear peptide motifs in tumour suppressor proteins 

Some tumour suppressor genes that are most commonly found to be mutated in patients with a hereditary predisposition to cancer are involved in repairing DNA damage in cells. However, we still do not understand exactly how many DNA repair proteins work at the molecular level, how drug resistance can develop in DNA repair-deficient tumours, nor why mutations in the intrinsically disordered regions of these proteins outside their known protein domains can predispose to cancer.

There is thus an urgent need to do more basic research into how DNA repair proteins function at the molecular level in order to understand potential drug resistance mechanisms as well as identify additional drug targets when resistance to radiotherapy and chemotherapy develops. The aim of this project is to identify novel protein interactors for the highly evolutionarily conserved but as-yet uncharacterized short linear peptide motifs in DNA repair proteins.

 

Thomas Lanyon-Hogg, Department of Pharmacology

Development of novel Hedgehog acyltransferase inhibitors from HTS hits to lead series

Hedgehog (Hh) signalling drives growth and is activated in several cancers. Hedgehog acyltransferase (HHAT) activity is required for Hh signalling, making HHAT an attractive target for inhibition. This project will build on the labs existing success in order to develop the most potent HHAT inhibitors to-date.

 

Val Macaulay, Ian Mills & Jack Mills, Department of Oncology & Nuffield Department of Surgical Sciences

Investigating nuclear IGF-1R function in clinical prostate cancers

 Insulin-like growth factors (IGFs) play key roles in prostate cancer biology. Type 1 IGF receptors (IGF-1Rs) are up-regulated in primary cancer and associated with lethal castrate-resistant prostate cancer (CRPC). This project aims to understand how nuclear IGF-1R regulates expression of genes contributing to cancer cell growth, androgen response and therapy resistance in vivo.

 

Wayne Paes et al., Centre for Cellular and Molecular Physiology, Nuffield Department of Medicine

Empirical determination of molecular biomarkers for precision-based immunotherapy in colorectal cancer

 Immune checkpoint inhibitors (ICIs) are only efficacious in ~15% of CRC patients while tumours in ~85% of patients remain innately resistant to ICI therapy. This pilot study aims to identify and correlate novel biomarkers in Immune Checkpoint Inhibitor (ICI)-sensitive and ICI-refractory colorectal cancer subsets at multiple levels. Characterisation of subsets will allow for identification of which are most responsive to ICIs and identify new potential therapeutic targets for those that are not.

 

Shijie Cai et al., Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine

Identification of small molecule inhibitors and synthetic lethality for GTP cyclohydrolase in triple-negative breast cancer

Triple-negative breast cancer (TNBC) accounts for about 10-15% of all breast cancer, with over 8000 cases diagnosed every year in the UK and estimated 1.7 million new cases worldwide. TNBC differs from other types of breast cancer in that they grow and spread faster. Chemotherapy is still the mainstay therapeutic option; however, patients suffer a high rate of distant recurrence and death. Thus, there is an unmet need to develop new small molecule inhibitors for TNBC therapy. GTPCH is a recently identified protein that drives TNBC growth. This project will identify small molecule inhibitors and synthetic lethal genes for GTPCH and enable the researchers to develop new inhibitors targeting TNBC.

Dr Lennard Lee awarded ACP McElwain Prize for contributions to medical oncology

Dr Lennard Lee, Academic Clinical Lecturer at the University of Oxford, has been awarded the 2020 Association of Cancer Physicians (ACP) McElwain Prize for his contribution to the development of Medical Oncology in the UK.

During the COVID-19 pandemic, Dr Lee’s contributions were best reflected in his creation and implementation of a national prospective observational cohort study of cancer patients during the COVID-19 pandemic, the UK Coronavirus Cancer Monitoring Project (UK CCMP). This was one of the largest global registries and the first to identify that cancer treatments can be safely delivered during a COVID-19 pandemic.

The initial phase of the project has been successfully achieved with the roll out and implementation of the UK CCMP emergency observational response network, as well as studies to determine those in our population who are most at risk – such as blood cancer patients.

Thanks to this project, the UK oncology community now has the tools and the mechanism to learn from each case of COVID-19 in cancer patients and the evidence required to bring about clinical management/service/treatment decision changes to improve the outcomes of cancer patients. The data from this project has helped form the guidelines which have been published from NHS England about the resumption of cancer services and led to the return of near-normal chemotherapy prescribing levels.

Building on the success of this work, Lennard is now leading on further studies to understand and better safeguard cancer patients during the pandemic. He has co-launched projects on COVID-19 vaccine efficacy, understanding how this is impacted by cancer treatments, and studies to identify other effective COVID-19 risk reduction interventions.

Lennard Lee said

“I am honoured to receive this award on behalf of all the clinicians and researchers who took part in the UKCCMP. The work by the UK oncology community had global impact, demonstrating that cancer patients can be treated safely during the pandemic. No one should be denied appropriate cancer treatments and it is important that we continue to deliver research excellence in order to protect the vulnerable during this pandemic”.

For more information about the UK CCMP see here.

Adrian Hill elected to Royal Society

Professor Adrian Hill, Director of the Jenner Institute (Nuffield Department of Medicine), has become a Fellow of the Royal Society for his leading role in the design and development of new vaccines for globally important infectious diseases over the course of over 25 years.

One of his most important developments has been the spin out of Vaccitech, which he co-founded in 2016, to capitalise on the discovery of ChAdOx. The chimp cold virus, ChAdOx, became a weapon of choice against what the World Health Organization called “Disease X” – a hypothetical future pathogen with epidemic or pandemic potential.

ChAdOx is a viral vector which safely mimics viral infection in human cells and elicit antibody and T cell responses to pathogens and tumours. Thus far, ChAdOx has already been applied in cancers (prostate), malaria, and most recently, the AstraZeneca-Oxford vaccine for Sars-Cov-2.

Through his work, Professor Hill has demonstrated the applications of adenoviruses in immunisation regimes supporting new vaccination approaches for a variety of disease, many of which have previously not had treatment options available.

Professor Hill becomes one of 6 new Oxford researchers to join the Royal Society. Read about them here.

Studying viral genetics to aid liver cancer early detection

Chronic Hepatitis C virus (HCV) infection causes liver damage and is a significant risk factor for liver cancer. There are now cures available for chronic HCV infection and the World Health Organisation has set a target to eliminate HCV by 2030. However, although curing HCV reduces the risk of liver cancer, individuals with a history of chronic HCV infection remain at higher risk.

There are multiple types of HCV that differ in their genetic sequences. Previous research has established that not all HCV genotypes present the same level of risk for liver cancer. The next step is to discover which particular viral genetic motifs are most associated with liver cancer so the HCV-infected individuals who are at the highest risk of liver cancer can be identified. This will enable more targeted surveillance to detect liver cancer earlier when treatment is more likely to be successful.

Professor Ellie Barnes and Dr Azim Ansari (Nuffield Department of Medicine) have been awarded funding as part of a wider Wellcome Trust Collaborative Award led by Professor Graham Foster (Queen Mary’s University, London) to study anti-viral drug resistance and long-term effects of HCV in Pakistan. HCV infection is highly prevalent in Pakistan with up to 20% of the population infected in hotspot regions.

A cohort of ~500 individuals with HCV-associated liver cancer will be recruited and samples will be collected for viral whole genome sequencing. The Oxford team will then analyse these sequences, comparing to people with HCV infection but not cancer, to identify any genetic patterns that are linked to cancer.

This work complements the recently launched Cancer Research UK-funded DeLIVER programme which, among other features, will study host and viral genetics in a cohort of individuals with HCV and liver cancer in the UK.

Christina Ye awarded CRUK pre-doctoral fellowship

Immune related toxicity is a common side effect of treatment with Immune Checkpoint Blockers for cancer – but the degree to which the development of these side effects is related to overall oncological outcome is unclear. As an Academic Foundation Programme Trainee within OUCAGS (https://www.oucags.ox.ac.uk), I had a four month block of time to work in a lab to gain experience of research. I worked with Dr Benjamin Fairfax’s group in the WIMM/Department of Oncology to explore the relationship between immune toxicity and clinical outcomes. Working with other members of the group, and Dr Anna-Olsson Brown in Liverpool, we found that patients who developed immune related toxicity appeared to have better long-term clinical outcomes including overall survival. Indeed, we found the development of toxicity was a key predictor of the cancer responding to treatment. This work is currently in-press in the British Journal of Cancer.

This period of time in the lab stimulated my interest in research and helped in my decision to apply for an Academic Clinical Fellowship in Dermatology. I was successful in this and I have a further nine months of protected research built into my training this year, which I again plan to spend working in Ben’s group. As a trainee dermatologist I am particularly intrigued by the rash patients frequently develop when they first receive immunotherapy. There is evidence to suggest that another side effect of immunotherapy, colitis, is secondary to the activation of resident memory T cells. Conversely, when you look at the gene expression in CD8 T cells after treatment with checkpoint blockers you can see up-regulation of genes involved in skin trafficking. I will explore whether this rash is indicative of T cell trafficking to the skin, or activation of resident memory T cells, or something completely separate.

Cancer Research UK awards biannual pre-doctoral research bursaries, aimed at providing ‘short term funding to allow clinicians and other health professionals to get involved in research projects early in their career’. Ben encouraged me to apply to this CRUK scheme to further explore the mechanistic basis of the rash in immunotherapy and I am very grateful to have been awarded this funding. Personally I am hoping to gain training in immunological techniques and bioinformatic analysis during this period, and I hope the results we generate will provide further insights into the cells cancer immunotherapy affects and how it works.

Oxford Cancer alumni’s biotech success

Scenic Biotech was founded in March 2017 as a spin-out of the University of Oxford and the Netherlands Cancer Institute. The company is based on the Cell-seq technology developed by co-founders Sebastian Nijman and Thijn Brummelkamp in their academic labs.

Cell-seq is a large-scale genetic screening platform that allows the identification of genetic modifiers – or disease suppressors – that act to decrease the severity of a disease. These disease-specific genetic modifiers are difficult to identify by more traditional population genetics approaches, especially in the case of rare genetic diseases. By mapping all the genetic modifiers that can influence the severity of a particular disease, Cell-seq unveils a new class of potential drug targets that can be taken forward for drug development.

In a deal worth $375m, Scenic Biotech has recently entered into a strategic collaboration with Genentech, a member of the Roche Group. This will enable discovery, development and commercialisation of novel therapeutics that target genetic modifiers.

Oxfordshire-based SCAN pathway wins BMJ award

Every year, the British Medical Journal (BMJ) runs a competition to find the cancer care team that has developed new approaches to improve cancer diagnosis and treatment. This year, six teams were shortlisted from across the UK and on the 7th October it was announced that the Oxfordshire-based SCAN pathway had won this year’s award.

The Suspected CANcer (SCAN) pathway is designed to accelerate cancer diagnosis in patients with non-specific cancer symptoms. The UK performs worse than many other developed nations in terms of cancer survival and this is in part due to the fact that 21% of cancers are diagnosed after emergency presentation, when they are often at a later stage and more difficult to treat successfully.

In an effort to improve these statistics, urgent referral pathways for suspected cancer have been developed for symptoms specific to one cancer site. However, one in five people diagnosed with cancer only ever report non-specific symptoms of cancer, such as unexplained weight loss, fatigue, nausea, or abdominal pain. These people often experience delays due to being referred sequentially to multiple different tumour site-specific clinics before receiving a diagnosis. The SCAN team identified this unmet need and designed and implemented a new diagnostic pathway that straddles primary and secondary care for patients with non-specific but concerning cancer symptoms.

Patients are referred by their GP to the pathway based in the Churchill Hospital, Oxford, where they are investigated with a whole body computed tomography (CT) scan and undergo blood and stool testing. The outcome of these tests directs the patient to the most appropriate clinical expertise to reach a diagnosis as quickly as possible.

Since its implementation across Oxfordshire in November 2017, the SCAN pathway has seen 2148 patients and diagnosed 201 incidences of cancer, most commonly lung, bowel, pancreas, lymphoma and breast. In addition to cancer diagnoses, the SCAN pathway has diagnosed a large number of serious non-cancer conditions, including tuberculosis, endocrine diseases and inflammatory bowel disease.

“One of the unique features of the SCAN Pathway is that for the remaining patients who do not receive a cancer diagnosis, we offer GPs the option for these patients to have a general medical review in a further attempt to reduce onward referrals.”

  • Julie-Ann Moreland, Macmillan Project Manager and SCAN Navigator, Oxford Radiology Research Unit

Since the SCAN pathway’s inception, the number of GP surgery visits and secondary care referrals prior to receiving a cancer diagnosis decreased by approximately 4-fold, saving a large number of NHS appointments, and the time to diagnosis has reduced. Patients have also responded positively about the service in patient satisfaction questionnaires.

“Prior to the SCAN pathway, patients with non-specific symptoms were having to go to the GP on average 7.8 times and be referred to numerous secondary care clinics before receiving a diagnosis. The SCAN pathway decreases the time to diagnosis and allows patients to start receiving important treatments earlier. This will not only improve patient outcomes but will also reduce the anxiety experienced by patients while waiting for a diagnosis”

 

 “I am delighted that the SCAN team have received this recognition from the BMJ. The judges made a special mention of the holistic care that the clinical team works so hard to provide. Given its success, we are introducing the pathway across the Thames Valley Cancer Alliance and other regions. We are gathering data as we go so we can learn how to improve the service for patients.”

  • Dr Brian Nicholson, Academic GP Lead, Nuffield Department of Primary Care Health Sciences

 

“The development and implementation of the SCAN Pathway has been the result of hard work and collaborative teamwork with passionate people who have strived to develop a service focusing on improving the experience for patients.

“To even be short listed for this award is an incredible achievement and so to win it has been a fantastic and unexpected surprise. We are all very proud of this new pathway and this is a brilliant way to receive recognition and celebrate that.”

  • Zoe Kaveney, Cancer Programme Manager at Oxfordshire Clinical Commissioning Group

 

The SCAN pathway was supported by the Accelerate, Coordinate, Evaluate (ACE) programme funded by NHS England, Cancer Research UK and Macmillan, and the Oxfordshire Clinical Commissioning Group.

Prof. Ellie Barnes comments on the 2020 Nobel Prize for Medicine

Prof Ellie Barnes comments on the recent Nobel Prize in Medicine, awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice for their discovery of the Hepatitis C virus, a major global health problem and a cause of cancer

In 1989, Harvey J. Alter, Michael Houghton and Charles M. Rice used what at the time were state-of-the-art technologies available to identify the virus that causes Hepatitis C infection. This ground-breaking discovery allowed for the development of blood tests to diagnose the Hepatitis C Virus (HCV) and saved millions of lives over the last 40 years.

Testing for HCV has enabled the discovery of chronic infections that results from the Hepatitis C virus. Currently 71 million people are living with HCV, as there is no vaccine to prevent infection. HCV remains a silent disease that is often only diagnosed until symptoms of late-stage liver disease develop. In many cases, it goes undetected until severe complications occur, the most serious of which is hepatocellular carcinoma (HCC). By this point, existing treatments are often less effective at clearing the infection.

Hepatocellular carcinoma is the most common type of primary liver cancer, which is common in those who have had liver scarring due to Hepatitis B and C infections. 400,000 people globally die each year from HCV, with hepatocellular carcinoma continually on the rise. As a result, viral hepatitis is still one of the most serious global pandemics at large. Due to the lack of an effective HCV vaccine and early detection methods for the diagnosis of hepatocellular carcinoma, it is crucial to develop techniques that can aid its early detection and thereby increase the survival rate of cancer patients.

Prof Ellie Barnes at the Nuffield Department of Medicine, leads the DeLIVER study for the early detection of hepatocellular carcinoma that builds on the seminal work as recognised with this year’s Nobel Prize. On the topic of this year’s Nobel Prize winners, she says:

“Now, we need to repeat what those Nobel Prize winners did in 1989 for liver cancer. Like them, we can use today’s new advances in imaging and molecular technology to identify hepatocellular carcinoma at an earlier stage when it is still curable.

“The techniques to do this have advanced remarkably over the last 40 years and it should be possible, with carefully designed patient cohorts and inter-disciplinary effective co-working. By building on the work of Alter, Houghton and Rice, we can do it.”

The risk of liver cancer is increased by viral hepatitis infections, alcohol and obesity, causing the immune system to attack the liver leading to scarring and liver cirrhosis. Monitoring of people with these conditions can reduce mortality but current diagnostic tests for hepatocellular carcinoma fail to detect cancer in many cases.

The DeLIVER team is building on the work of Nobel Prize winners through the use of state-of-the-art multiparametric imaging, viral genetics, and liquid biopsy technologies (such as TAPS) to identify the early indicators of liver cancer by studying people at risk, such as those with Hepatitis C, over several years.

About DeLIVER

DeLIVER is a CRUK-funded programme led by Professor Ellie Barnes that aims to better understand the pre-cancerous changes in the liver and use this knowledge to inform new technologies for early HCC detection. The study will receive patient input from the British Liver Trust and the Hepatitis C Trust.

You can read more about it on the OxCODE website here.

Prof Anna Schuh wins Vice-Chancellor Innovation Award

Anna and her team wins the Teamwork award for their work on improving the outcome of children with blood diseases in sub-Saharan Africa

Professor Sir Peter Ratcliffe elected as an AACR Academy Fellow

Sir Peter joins the ranks of the American Association for Cancer Research’s finest scientists.